Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL

doi:10.1073/pnas.0605934104

Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL

*Program in Neuroscience and
Departments of ^†Ophthalmology and Visual Sciences and
^¶Human Genetics, University of Michigan, Ann Arbor, MI 48105;
^‡Fondazione GB Bietti, 00161 Rome, Italy; and
^§Italian National Research Council (CNR), Neuroscience Institute, 56100 Pisa, Italy

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 29, 2006 (received for review July 13, 2006)

Abstract

Networks of transcriptional regulatory proteins dictate specification of neural lineages from multipotent retinal progenitors. Rod photoreceptor differentiation requires the basic motif–leucine zipper (bZIP) transcription factor NRL, because loss of Nrl in mice (Nrl ^−/−) results in complete transformation of rods to functional cones. To examine the role of NRL in cell fate determination, we generated transgenic mice that express Nrl under the control of Crx promoter in postmitotic photoreceptor precursors of WT and Nrl ^−/− retina. We show that NRL expression, in both genetic backgrounds, leads to a functional retina with only rod photoreceptors. The absence of cones does not alter retinal lamination, although cone synaptic circuitry is now recruited by rods. Ectopic expression of NRL in developing cones can also induce rod-like characteristics and partially suppress cone-specific gene expression. We show that NRL is associated with specific promoter sequences in Thrb (encoding TRβ2 transcription factor required for M-cone differentiation) and S-opsin and may, therefore, directly participate in transcriptional suppression of cone development. Our studies establish that NRL is not only essential but is sufficient for rod differentiation and that postmitotic photoreceptor precursors are competent to make binary decisions during early retinogenesis.

Footnotes

^‖To whom correspondence should be addressed at:
Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105.
E-mail: swaroop{at}umich.edu
Author contributions: E.C.T.O., E.S., and A.S. designed research; E.C.T.O., N.K., E.N., H.K., and E.S. performed research; E.C.T.O., N.K., E.N., H.K., E.S., and A.S. analyzed data; and E.C.T.O., E.S., and A.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0605934104/DC1.
Abbreviations:

En,

embryonic day n;

ERG,

electroretinogram;

NRE,

Nrl response element.
Freely available online through the PNAS open access option.